Summary Age-related diseases are the major causes of morbidity and mortality in Western society, and aging is a significant risk factor for the development of Alzheimer's disease (AD). Calorie restriction (CR), a dietary intervention which extends lifespan while delaying or preventing age-related disease, can slow or prevent AD in animal models, but reduced-calorie diets are notoriously difficult to sustain. Over the past decade, significant progress has been made in identifying small molecules that can mimic some of the benefits of a CR diet and extend lifespan and/or healthspan. There is growing evidence that these geroprotectors may be able to treat or prevent Alzheimer's disease, but significant questions remain. This proposal, which is responsive to PAR-18- 596, will address major outstanding questions surrounding the use of geroprotectors for AD, as we address the high-priority topic of a ?Geroscience Approaches to Alzheimer's Disease.? Here, we will rigorously test four geroprotectors covering a broad range of mechanisms including the inhibition of mTOR, the activation of AMPK, and the induction of sirtuins in two mouse models of AD. As research into geroprotectors thus far has utilized models of disease based on mutations identified in early onset AD, we will perform a comparative study of these geroprotectors in both an early onset mouse model of AD, the 3xTg mouse, and a novel mouse model of late-onset AD recently developed by the MODEL-AD consortium. Late- onset AD represents the majority of human cases of AD, and thus assessing the efficacy of geroprotectors in late-onset models of AD is critical. The risk of late-onset AD is significantly increased by the development of type 2 diabetes, and the prevalence of both obesity and diabetes continues to increase in the elderly. Importantly, many geroprotectors affect metabolic health, altering glycemic control and body composition. We will therefore perform the first ever assessment of geroprotectors on cognition, AD pathology, frailty, and the overall metabolic health of mouse models of AD with diet-induced obesity. Finally, glucose metabolism is disrupted in the brains and neurons of AD patients, and recent work has identified defects in glucose uptake and mitochondrial dysfunction. We will leverage a set of novel metabolic biosensors to identify the precise nature of the metabolic signaling defects in the neurons of early and late-onset mouse models of AD, and further determine if geroprotectors can restore normal metabolism at the level of the single cell. In the long term, the work proposed here will significantly advance the concept of a geroscience approach to AD, improving our understanding of the efficacy of geroprotectors in early and late-onset models of AD, in lean mice and in the context of diet-induced obesity, and at the level of the whole organism and single neuron. Not only will we identify geroprotectors for future clinical evaluation, but we will establish an overall approach that will be invaluable for the preclinical evaluation of strategies to reverse or prevent AD in the future.